Wnt signaling controls body axis formation and organ formation in early development; cell proliferation and cell differentiation after birth; and the like. It has been known that activation of the Wnt signaling induces various cell responses through a number of intracellular signaling pathways (Non-Patent Document 1). The most known among the Wnt signaling pathways is the β-catenin pathway. β-catenin, which is stored in the cytoplasm in a normal condition, is transferred to the nucleus by Wnt stimulation, and bound to T cell factor/lymphocyte enhancing factor (TCF/LEF) that are transcription factors to induce expression of genes such as AXIN and c-MYC. It has been known that when there is an abnormality in the Wnt signaling pathway, various diseases are caused. In particular, genetic mutations of β-catenin, APC (adenomatous polyposis coli), AXIN and the like, which are deeply related to the onset of cancer as well as are constituent proteins of the Wnt signaling pathway, have been reported in human cancer cases (Non-Patent Document 2). In these cancer cells, abnormal accumulation of β-catenin and various gene expressions promoting cell growth are observed.
It has been elucidated that the Wnt/β-catenin signaling pathway is also involved with maintenance and differentiation of undifferentiated potential of stem cells besides early development and organ formation (Non-Patent Documents 3, 4). Of the cancer cells, the presence of those cells having the similar characteristics to those of stem cells (cancer stem cells) has been reported. It is considered that cancer stem cells are sources of producing a large number of peripheral cancer cells by differentiation, while maintaining autologous cells in cancer tissue by autonomous replication. Not only in normal cells but also in cancer cells, the Wnt/β-catenin signaling pathway is involved with maintenance of their stemness. It is considered that since cancer stem cells are resistant to treatment by general anticancer drugs, a very small number of cancer stem cells survived after the anticancer drug treatment cause recurrence and metastasis of cancer (Non-Patent Documents 5, 6). Since the cancer stem cells are considered to be causes of cancerogenesis, cancer metastasis, and cancer recurrence, they are also referred to as tumor initiating cells, cancer stem-like cells, stem-like cancer cells, highly tumorigenic cells or super malignant cells.
Therefore, compounds inhibiting the Wnt/β-catenin signaling pathway are useful for treatment of diseases, with which the Wnt signaling is involved, in particular cancer, and also useful for prevention of metastasis and recurrence of tumors by targeting cancer stem cells.
Various quinazoline derivatives have hitherto been known. In addition to Patent Document 1 by the applicant, Patent Document 2, Patent Document 3 and the like have been reported. However, there is no description of quinazoline derivatives of the present invention, and there is no report stating that they inhibit the Wnt/β-catenin signaling pathway either.